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Disrupted sleep speeds up cancer

Researchers in the US found of two groups of mice given the same cancer-inducing
treatment, the group whose sleep was disrupted developed larger, more aggressive tumors than
the well-rested mice.

In the journal Cancer Research, the team also reports how they found the immune
system of the sleep-disrupted mice was less effective at fighting the early stages of cancer
than the immune system of the well-rested mice.

Study director Prof. David Gozal says:

"It's not the tumor, it's the immune system. Fragmented sleep changes how the immune system
deals with cancer in ways that make the disease more aggressive."

"Fortunately, our study also points to a potential drug target," he adds, describing how
they found a biological messenger - the protein TLR4 - helps to activate the innate immune
system.

He says TLR4 seems to act as a "lynchpin" between sleep loss and cancer promotion - the
effects of fragmented sleep they focused on "were not seen in mice that lacked this
protein."

First study to show in animals how fragmented sleep affects tumors

The researchers believe their study, which was funded by the National Institutes of Health,
is the first to show, in an animal model, how fragmented sleep directly impacts tumor growth
and aggressiveness.

The study came about because research linking sleep apnea and death from cancer caught the
attention of Prof. Gozal, an authority on the consequences of sleep apnea, and its hallmark,
disrupted sleep.

So he and his colleagues, from the Universities of Chicago and Louisville, carried out a
series of experiments using lab mice to look at this more closely.

During the day, when the small groups of mice were normally asleep in their cages, a silent,
motorized brush passed through half the cages, forcing the mice to wake up and then go back to
sleep. The rest of the mice were left in peace.

After a week, the mice received injections of tumor cells that caused all of them to develop
tumors. Four weeks later, the researchers examined the mice.

Mice with disrupted sleep had bigger, more aggressive tumors

The researchers found that the mice whose sleep was disrupted had tumors twice the size of those in the mice
that slept normally.

And then in a further experiment, where they implanted tumor cells in the mice's thigh
muscles - which usually restricts cancer growth - in the mice with disrupted sleep, the tumors
were more aggressive and invaded surrounding tissue.

Prof. Gozal explains that, usually in muscle, tumors become encased in a tissue capsule rather like
a scar: they become "little spheres," with a clear separation between cancerous and normal
tissue.

However, in the mice that had disrupted sleep, the tumors had pushed through the capsule and
gone into the muscle and bone.

Differences appear to be driven by immune cells

When they looked at the underlying molecular mechanisms, the team found the difference in
the two groups of mice appears driven by immune cells called tumor-associated macrophages or
TAMs.

TAMs work in one of two ways, depending on what signals they receive. One way causes them to
eliminate cancer cells, while the other way causes them to help the growth of new blood vessels
for the tumor.

The team found the well-rested mice had mostly TAMs working in the core of the tumors,
eliminating cancer cells. But in the sleep-disrupted mice, the TAMs, which were all around the outside edges of the
tumors, were busy promoting blood vessel growth to bring a blood supply to help the tumors
grow.

The sleep-disrupted mice also had high levels of TLR4. This signalling protein seems to team
up with two others, MYD88 and TRIF, to cause the TAMs in the sleep-disrupted mice to be more of
the type that favor tumor growth.

So in a final set of experiments, the researchers injected cells into mice bred to lack one
of these three signalling proteins.

They found the tumors grew a little less rapidly in sleep-disrupted mice lacking MYD88 or
TRIF. But in sleep-disrupted mice lacking TLR4, the tumors grew no faster than in well-rested
mice.

It appears that TLR4 is a major culprit of tumor growth, as Prof. Gozal explains:

"When we injected tumor cells into mice that lacked TLR4, the differences between
undisturbed and sleep-fragmented mice disappeared."

He believes the findings offer a biological explanation for observed links
between disrupted sleep and cancer, noting that "the take home message is to take care of your sleep quality and quantity like you take care
of your bank account."

The US Centers for Disease Control and Prevention (CDC) says around 70 million Americans have chronic sleep problems. Considering how this sleep disruption,
like cancer, strikes more in middle-aged and older people, the authors say their findings have
"far-reaching implications." The team now plans to look at whether sleep disruption affects how readily cancer spreads
(metastasis), and response to chemotherapy.

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